Search for a schizophrenia susceptibility locus on chromosome 17

Carroll, Liam Stuart 2007. Search for a schizophrenia susceptibility locus on chromosome 17. PhD Thesis, Cardiff University.

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Abstract

The search for genetic variants that alter the risk of developing schizophrenia has met with little success (Owen et al., 2005a) with the best example coming from a large multiply affected pedigree (Blackwood et al., 2001, Millar et al., 2000, St Clair et al., 1990). In this study a genome-wide significant schizophrenia linkage region in a single pedigree (Williams et al., 2003a) has been refined to an 11.7Mb region at 17q23-q24 where all 6 affected males share 21 consecutive microsatellite marker genotypes. Analysis of this region by oligonucleotide-array comparative genome hybridisation shows that no large deletions explain the linkage signal. High-density genotyping identified a region of homozygosity present in C702 affecteds that was not identified in 2709 individuals from the UK. This rare diplotype encompasses the 3' of the gene encoding Protein Kinase C Alpha (PRKCA), implicated in the pathogenesis of schizophrenia and related disorders (Mimics et al., 2001, Hahn and Friedman, 1999, Birnbaum et al., 2004). Mutation screening of PRKCA in the linked pedigree C702 identified an exonic haplotype with a minor allele frequency of 0.003, which is homozygous in affected individuals. The haplotype is associated in a UK case-control sample with major mental illness (p=0.05. OR=l .8) due to risk in males (p=0.005. OR=3.9). Also, the pedigree C702 genotype was not observed in -9000 Europeans. Association mapping of PRKCA using schizophrenia and psychosis case-control samples from Europe identified a common associated allele (rs3803821, meta analysis p=0.02, OR=l.l) that shows significant overtransmission in a trios sample (p=0.03). Therefore, PRKCA may represent the locus causing the pedigree C702 linkage signal and contains genetic variation associated with schizophrenia and related disorders.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
ISBN:	9781303182310
Date of First Compliant Deposit:	30 March 2016
Last Modified:	09 Aug 2024 15:34
URI:	https://orca.cardiff.ac.uk/id/eprint/55702

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